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Susceptibility to malignant hyperthermia: Evaluation and management

Ronald S Litman, DO, FAAP
Section Editor
Stephanie B Jones, MD
Deputy Editor
Marianna Crowley, MD


Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent or succinylcholine [1-3]. Patients who are susceptible to MH have skeletal muscle receptor abnormalities that allow excessive myoplasmic calcium to accumulate in the presence of certain anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis [4-6].

Susceptibility to MH (MHS) may arise de novo or be inherited in an autosomal dominant fashion. It is suspected in individuals with a history of a clinical event strongly suspicious for an acute MH crisis or with a family history of susceptibility. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MHS patients and prompt administration of dantrolene when an acute event occurs have reduced the mortality associated with malignant hyperthermia from historic rates of 70 percent to <1 percent [7,8].

This topic will review the genetic basis and testing for MHS and the safe administration of anesthesia to MHS patients. The pathophysiology, clinical manifestations, diagnosis, and management of an acute MH crisis are discussed elsewhere. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis".)


The prevalence of susceptibility to malignant hyperthermia (MHS) in the general population is unknown, though it is estimated at 1:2000 by the Malignant Hyperthermia Association of the United States [9]. Published rates of susceptibility vary widely depending upon the population studied and the manner in which MHS was determined. Prevalence is most often studied in family cohorts of patients known to be MHS; rates range from 1:200 to 1:5000 in these cohorts [10,11]. Incomplete penetrance and variable expressivity lead to far fewer cases of clinically significant MH than gene prevalence rates would suggest.


Susceptibility to malignant hyperthermia (MHS) is conferred by mutations of genes associated with proteins controlling levels of cytosolic calcium and, therefore, skeletal muscle contraction [12]. Approximately one-half of cases are inherited in an autosomal dominant fashion; others are presumed to be new mutations. Genes responsible for coding proteins of the calcium channel in the sarcoplasmic reticulum are most commonly affected: the ryanodine receptor (RYR1) and the closely associated dihydropyridine receptor (DHP). The likelihood that a susceptible patient will develop MH depends upon the specific type of receptor mutation [13]. Because of incomplete genetic penetrance and variable expressivity, there is great variability in the clinical expression of the syndrome among individuals and between anesthetic episodes in the same individual [14,15]. (See "Malignant hyperthermia: Clinical diagnosis and management of acute crisis", section on 'Clinical presentation'.)


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Literature review current through: Sep 2016. | This topic last updated: Jan 8, 2016.
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  1. Denborough M. Malignant hyperthermia. Lancet 1998; 352:1131.
  2. Simon HB. Hyperthermia. N Engl J Med 1993; 329:483.
  3. Litman RS, Rosenberg H. Malignant hyperthermia-associated diseases: state of the art uncertainty. Anesth Analg 2009; 109:1004.
  4. Wappler F. Malignant hyperthermia. Eur J Anaesthesiol 2001; 18:632.
  5. MacLennan DH, Phillips MS. Malignant hyperthermia. Science 1992; 256:789.
  6. Lee-Chiong TL Jr, Stitt JT. Disorders of temperature regulation. Compr Ther 1995; 21:697.
  7. Larach MG, Brandom BW, Allen GC, et al. Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States. Anesthesiology 2008; 108:603.
  8. Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology 2009; 110:89.
  9. http://www.mhaus.org/faqs/about-mh (Accessed on April 16, 2013).
  10. Bachand M, Vachon N, Boisvert M, et al. Clinical reassessment of malignant hyperthermia in Abitibi-Témiscamingue. Can J Anaesth 1997; 44:696.
  11. Monnier N, Krivosic-Horber R, Payen JF, et al. Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 2002; 97:1067.
  12. Davis PJ, Brandom BW. The association of malignant hyperthermia and unusual disease: when you're hot you're hot or maybe not. Anesth Analg 2009; 109:1001.
  13. Carpenter D, Robinson RL, Quinnell RJ, et al. Genetic variation in RYR1 and malignant hyperthermia phenotypes. Br J Anaesth 2009; 103:538.
  14. Robinson RL, Anetseder MJ, Brancadoro V, et al. Recent advances in the diagnosis of malignant hyperthermia susceptibility: how confident can we be of genetic testing? Eur J Hum Genet 2003; 11:342.
  15. Eltit JM, Bannister RA, Moua O, et al. Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor. Proc Natl Acad Sci U S A 2012; 109:7923.
  16. Sambuughin N, Holley H, Muldoon S, et al. Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population. Anesthesiology 2005; 102:515.
  17. Stewart SL, Hogan K, Rosenberg H, Fletcher JE. Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet 2001; 59:178.
  18. MacLennan DH, Duff C, Zorzato F, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature 1990; 343:559.
  19. McCarthy TV, Healy JM, Heffron JJ, et al. Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2. Nature 1990; 343:562.
  20. Yang T, Ta TA, Pessah IN, Allen PD. Functional defects in six ryanodine receptor isoform-1 (RyR1) mutations associated with malignant hyperthermia and their impact on skeletal excitation-contraction coupling. J Biol Chem 2003; 278:25722.
  21. Broman M, Gehrig A, Islander G, et al. Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases. Br J Anaesth 2009; 102:642.
  22. Brandt A, Schleithoff L, Jurkat-Rott K, et al. Screening of the ryanodine receptor gene in 105 malignant hyperthermia families: novel mutations and concordance with the in vitro contracture test. Hum Mol Genet 1999; 8:2055.
  23. Girard T, Urwyler A, Censier K, et al. Genotype-phenotype comparison of the Swiss malignant hyperthermia population. Hum Mutat 2001; 18:357.
  24. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 1997; 60:1316.
  25. Rueffert H, Olthoff D, Deutrich C, et al. Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations. Acta Anaesthesiol Scand 2002; 46:692.
  26. Sei Y, Sambuughin NN, Davis EJ, et al. Malignant hyperthermia in North America: genetic screening of the three hot spots in the type I ryanodine receptor gene. Anesthesiology 2004; 101:824.
  27. https://emhg.org/genetics/mutations-in-ryr1/ (Accessed on September 29, 2014).
  28. Litman RS, Rosenberg H. Malignant hyperthermia: update on susceptibility testing. JAMA 2005; 293:2918.
  29. Vladutiu GD, Isackson PJ, Kaufman K, et al. Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Mol Genet Metab 2011; 104:167.
  30. Quane KA, Healy JM, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet 1993; 5:51.
  31. Sewry CA, Müller C, Davis M, et al. The spectrum of pathology in central core disease. Neuromuscul Disord 2002; 12:930.
  32. Klingler W, Rueffert H, Lehmann-Horn F, et al. Core myopathies and risk of malignant hyperthermia. Anesth Analg 2009; 109:1167.
  33. Zhang Y, Chen HS, Khanna VK, et al. A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet 1993; 5:46.
  34. Guis S, Figarella-Branger D, Monnier N, et al. Multiminicore disease in a family susceptible to malignant hyperthermia: histology, in vitro contracture tests, and genetic characterization. Arch Neurol 2004; 61:106.
  35. D'Arcy CE, Bjorksten A, Yiu EM, et al. King-denborough syndrome caused by a novel mutation in the ryanodine receptor gene. Neurology 2008; 71:776.
  36. Stamm DS, Aylsworth AS, Stajich JM, et al. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am J Med Genet A 2008; 146A:1832.
  37. Parness J, Bandschapp O, Girard T. The myotonias and susceptibility to malignant hyperthermia. Anesth Analg 2009; 109:1054.
  38. Tobin JR, Jason DR, Challa VR, et al. Malignant hyperthermia and apparent heat stroke. JAMA 2001; 286:168.
  39. Figarella-Branger D, Kozak-Ribbens G, Rodet L, et al. Pathological findings in 165 patients explored for malignant hyperthermia susceptibility. Neuromuscul Disord 1993; 3:553.
  40. Bendahan D, Kozak-Ribbens G, Confort-Gouny S, et al. A noninvasive investigation of muscle energetics supports similarities between exertional heat stroke and malignant hyperthermia. Anesth Analg 2001; 93:683.
  41. Ryan JF, Tedeschi LG. Sudden unexplained death in a patient with a family history of malignant hyperthermia. J Clin Anesth 1997; 9:66.
  42. Köchling A, Wappler F, Winkler G, Schulte am Esch JS. Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia. Anaesth Intensive Care 1998; 26:315.
  43. Wappler F, Fiege M, Steinfath M, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology 2001; 94:95.
  44. Sambuughin N, Capacchione J, Blokhin A, et al. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet 2009; 76:564.
  45. Krivosic-Horber R, Dépret T, Wagner JM, Maurage CA. Malignant hyperthermia susceptibility revealed by increased serum creatine kinase concentrations during statin treatment. Eur J Anaesthesiol 2004; 21:572.
  46. Guis S, Bendahan D, Kozak-Ribbens G, et al. Rhabdomyolysis and myalgia associated with anticholesterolemic treatment as potential signs of malignant hyperthermia susceptibility. Arthritis Rheum 2003; 49:237.
  47. Gurnaney H, Brown A, Litman RS. Malignant hyperthermia and muscular dystrophies. Anesth Analg 2009; 109:1043.
  48. Benca J, Hogan K. Malignant hyperthermia, coexisting disorders, and enzymopathies: risks and management options. Anesth Analg 2009; 109:1049.
  49. Fricker RM, Raffelsberger T, Rauch-Shorny S, et al. Positive malignant hyperthermia susceptibility in vitro test in a patient with mitochondrial myopathy and myoadenylate deaminase deficiency. Anesthesiology 2002; 97:1635.
  50. Isaacs H, Badenhorst ME, Du Sautoy C. Myophosphorylase B deficiency and malignant hyperthermia. Muscle Nerve 1989; 12:203.
  51. Lobato EB, Janelle GM, Urdaneta F, Malias MA. Noncardiogenic pulmonary edema and rhabdomyolsis after protamine administration in a patient with unrecognized McArdle's disease. Anesthesiology 1999; 91:303.
  52. Bollig G, Mohr S, Raeder J. McArdle's disease and anaesthesia: case reports. Review of potential problems and association with malignant hyperthermia. Acta Anaesthesiol Scand 2005; 49:1077.
  53. Katsuya H, Misumi M, Ohtani Y, Miike T. Postanesthetic acute renal failure due to carnitine palmityl transferase deficiency. Anesthesiology 1988; 68:945.
  54. Hogan KJ, Vladutiu GD. Malignant hyperthermia-like syndrome and carnitine palmitoyltransferase II deficiency with heterozygous R503C mutation. Anesth Analg 2009; 109:1070.
  55. Ryan CA, Al-Ghamdi AS, Gayle M, Finer NN. Osteogenesis imperfecta and hyperthermia. Anesth Analg 1989; 68:811.
  56. Rampton AJ, Kelly DA, Shanahan EC, Ingram GS. Occurrence of malignant hyperpyrexia in a patient with osteogenesis imperfecta. Br J Anaesth 1984; 56:1443.
  57. Porsborg P, Astrup G, Bendixen D, et al. Osteogenesis imperfecta and malignant hyperthermia. Is there a relationship? Anaesthesia 1996; 51:863.
  58. Bojanić K, Kivela JE, Gurrieri C, et al. Perioperative course and intraoperative temperatures in patients with osteogenesis imperfecta. Eur J Anaesthesiol 2011; 28:370.
  59. http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/does-noonan-syndrome-increase-malignant-hyperthermia-susceptibility (Accessed on September 29, 2014).
  60. Martin S, Tobias JD. Perioperative care of the child with arthrogryposis. Paediatr Anaesth 2006; 16:31.
  61. Baines DB, Douglas ID, Overton JH. Anaesthesia for patients with arthrogryposis multiplex congenita: what is the risk of malignant hyperthermia? Anaesth Intensive Care 1986; 14:370.
  62. Hopkins PM, Ellis FR, Halsall PJ. Hypermetabolism in arthrogryposis multiplex congenita. Anaesthesia 1991; 46:374.
  63. Buzello W, Krieg N, Schlickewei A. Hazards of neostigmine in patients with neuromuscular disorders. Report of two cases. Br J Anaesth 1982; 54:529.
  64. Smego RA Jr, Durack DT. The neuroleptic malignant syndrome. Arch Intern Med 1982; 142:1183.
  65. Caroff SN, Rosenberg H, Fletcher JE, et al. Malignant hyperthermia susceptibility in neuroleptic malignant syndrome. Anesthesiology 1987; 67:20.
  66. Ward A, Chaffman MO, Sorkin EM. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs 1986; 32:130.
  67. Bello N, Adnet P, Saulnier F, et al. [Lack of sensitivity to per-anesthetic malignant hyperthermia in 32 patients who developed neuroleptic malignant syndrome]. Ann Fr Anesth Reanim 1994; 13:663.
  68. Strazis KP, Fox AW. Malignant hyperthermia: a review of published cases. Anesth Analg 1993; 77:297.
  69. Larach MG, Gronert GA, Allen GC, et al. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg 2010; 110:498.
  70. Bendixen D, Skovgaard LT, Ording H. Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test. Acta Anaesthesiol Scand 1997; 41:480.
  71. Larach MG, Localio AR, Allen GC, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology 1994; 80:771.
  72. Rosenberg H, Antognini JF, Muldoon S. Testing for malignant hyperthermia. Anesthesiology 2002; 96:232.
  73. Hopkins PM, Hartung E, Wappler F. Multicentre evaluation of ryanodine contracture testing in malignant hyperthermia. The European Malignant Hyperthermia Group. Br J Anaesth 1998; 80:389.
  74. Brandom BW, Bina S, Wong CA, et al. Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States. Anesth Analg 2013; 116:1078.
  75. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. The North American Malignant Hyperthermia Registry of MHAUS. Anesthesiology 1998; 88:579.
  76. Ording H, Brancadoro V, Cozzolino S, et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anaesthesiol Scand 1997; 41:955.
  77. Brandom BW. Genetics of malignant hyperthermia. ScientificWorldJournal 2006; 6:1722.
  78. Mitchell LW, Leighton BL. Warmed diluent speeds dantrolene reconstitution. Can J Anaesth 2003; 50:127.
  79. Ellis FR, Harriman DG, Keaney NP, et al. Halothane-induced muscle contracture as a cause of hyperpyrexia. Br J Anaesth 1971; 43:721.
  80. A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility. The European Malignant Hyperpyrexia Group. Br J Anaesth 1984; 56:1267.
  81. Fortunato G, Carsana A, Tinto N, et al. A case of discordance between genotype and phenotype in a malignant hyperthermia family. Eur J Hum Genet 1999; 7:415.
  82. Girard T, Treves S, Voronkov E, et al. Molecular genetic testing for malignant hyperthermia susceptibility. Anesthesiology 2004; 100:1076.
  83. http://www.mhaus.org/healthcare-professionals/be-prepared/preparing-the-anesthesia-machine (Accessed on April 15, 2013).
  84. Petroz GC, Lerman J. Preparation of the Siemens KION anesthetic machine for patients susceptible to malignant hyperthermia. Anesthesiology 2002; 96:941.
  85. Prinzhausen H, Crawford MW, O'Rourke J, Petroz GC. Preparation of the Dräger Primus anesthetic machine for malignant hyperthermia-susceptible patients. Can J Anaesth 2006; 53:885.
  86. Kim TW, Nemergut ME. Preparation of modern anesthesia workstations for malignant hyperthermia-susceptible patients: a review of past and present practice. Anesthesiology 2011; 114:205.
  87. Birgenheier N, Stoker R, Westenskow D, Orr J. Activated charcoal effectively removes inhaled anesthetics from modern anesthesia machines. Anesth Analg 2011; 112:1363.
  88. Gunter JB, Ball J, Than-Win S. Preparation of the Dräger Fabius anesthesia machine for the malignant-hyperthermia susceptible patient. Anesth Analg 2008; 107:1936.
  89. http://www.mhaus.org/healthcare-professionals/be-prepared/post-operative-procedure (Accessed on April 15, 2013).
  90. Pollock N, Langtont E, Stowell K, et al. Safe duration of postoperative monitoring for malignant hyperthermia susceptible patients. Anaesth Intensive Care 2004; 32:502.
  91. Barnes C, Stowell KM, Bulger T, et al. Safe duration of postoperative monitoring for malignant hyperthermia patients administered non-triggering anaesthesia: an update. Anaesth Intensive Care 2015; 43:98.
  92. http://www.mhaus.org/healthcare-professionals/mhaus-recommendations/parturient-with-mhs-partner (Accessed on April 16, 2013).